This invention relates to metal chelate protein conjugates and to an improved method of forming metal chelate protein conjugates.
There has been a continuing interest in the art in metal chelate protein conjugates both for therapeutic and for diagnostic purposes. Representative type conjugates are disclosed, inter alia, in U.S. Pat. Nos. 4,454,106 and 4,472,509. One such type of conjugate is a metal chelate monoclonal antibody conjugate. Other proteins including, for example, polyclonal antibodies, antigens and blood proteins can also be employed in the formation of a metal chelate protein conjugate.
In general, the prior art has formed a conjugate of a chelate and protein and thereafter mixed that conjugate with the metal to be chelated. Such system is feasible as described in U.S. Pat. No. 4,472,509. In order to provide a conjugate in which substantially all the metal is contained in the chelate, however, several precautions are necessary. As a threshold matter, the protein to be used should be essentially free of metals which chelate because the presence of those metals with the protein may block the desired chelating sites. In addition, protein has an inherent ability to adventitiously bind metal along the protein molecule. Such metal may be either strongly or weakly bound depending upon the metal thereby presenting a significant challenge in removing the adventitiously bound metals from the protein. Some of the adventitiously bound metals may be (and often are) released in vivo and, particularly in the case of radioactive metals, may produce an undesirable concentration of the metal in bone marrow or the like. A process for processing metal chelate protein conjugates for the removal of adventitiously bound metals is disclosed in U.S. Pat. No. 4,472,509.
There continues to be a need for effective metal chelate protein conjugates as well as an effective method for forming a metal chelate protein conjugate that does not require substantial protein pre-purification and/or subsequent processing to remove adventitiously bound metals.